Alzheimer?s disease is a burgeoning national epidemic and an effective treatment is urgently needed. It is now widely recognized that vascular disease contributes to Alzheimer?s disease and, in some cases, may be central to the process of neuronal degeneration. Cerebral amyloid angiopathy (CAA) is a vasculopathy produced when ?-amyloid forms a toxic encrustation on cerebral arterioles and capillaries; it independently contributes to cognitive impairment and predisposes elderly patients to intracerebral hemorrhage. CAA has emerged as a critical variable in the search for a treatment for Alzheimer?s disease, and is particularly important as mechanisms of cerebral ?-amyloid clearance are beginning to be better understood. Never-the-less, fundamental mechanisms of whether and how ?-amyloid undermines the structural integrity of vessels remain unknown. We propose to optimize and study a new mouse model of CAA induced by surgically implanting purified ?-amyloid seeds isolated from human cerebral microvessels with CAA into the cerebral ventricles of 5xFAD mice. Previous animal models of CAA are inadequate due to slow development of ?-amyloid pathology and minimal development of microvascular degeneration, whereas the current model develops robust CAA within 3 months of the injection along with other microvascular degeneration features. Our main goals are 1) to optimize this model and 2) use it to definitively assess for a link between vascular ?-amyloid deposition and microvascular degeneration. We will evaluate for microvascular degeneration using advanced microscopy techniques, including 3-dimensional mapping of the microvascular network using CLARITY and assessment of the stiffness of the extracellular matrix in arterioles affected by CAA using atomic force microscopy. We will also assess functional, neurobehavioral outcomes in this new model system. This work will answer fundamental questions about the link between vascular integrity and Alzheimer?s disease and provide a foundation for future work to better understand the molecular mechanisms of vascular fragility in CAA.
Alzheimer?s disease and cerebral amyloid angiopathy are important interacting neuropathologies that cause huge societal burden. Current animal models of cerebral amyloid angiopathy are sub-optimal, so we will investigate a new model that captures microvascular degeneration to determine if vascular ?-amyloid deposition is associated with vascular fragility, microischemia and neurobehavioral deficits. An effective model animal system is essential for developing a therapy for cerebral amyloid angiopathy.
